Download ADRENOCORTICAL DEFICIENCY

ADRENOCORTICAL
DEFICIENCY
Hasan AYDIN, MD
Endocrinology and Metabolism
Yeditepe University Medical Faculty
Definition
Deficient adrenal production of
glucocorticoids or mineralocorticoids
Cholesterol
Cholesterol desmolase
Steroidogenesis
17α-hydroxylase
Pregnenolone
17,20 lyase
17-Hydroxypregnenolone
DHEA
3β hydroxysteroid
dehydrogenase
Progesterone
17-Hydroxyprogesterone
Androstenedione
21β-hydroxylase
11-Deoxycorticosterone
11-Deoxycortisol
Testosterone
11β-hydroxylase
Corticosterone
Cortisol
Fasciculata
Aldosterone synthase
Aldosterone
Glomerulosa
Estradiol
Reticularis
Primary Adrenal Insufficiency
Causes
• Anatomic destruction of gland
• Metabolic failure in hormone production
• ACTH-blocking antibodies
• Mutation in ACTH receptor gene
• Adrenal hypoplasia congenita
Secondary Adrenal Insufficiency
• Hypopituitarism due to hypothalamic-pituitary
disease
• Suppression of H-P-A axis
- By exogenous steroid
- By endogenous steroid from tumor
Causes of Adrenal Insufficiency
Primary adrenal insufficiency
Secondary adrenal insufficiency
•
Autoimmune (70%of patients)
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Exogenous glucocorticoid withdawal
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Infections
Tuberculosis (20% of patients)
menincococcus,pnumococcus,
fungal,HIV
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Following cure of cushing’s sydrome
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Hypothalamic or pituitary disease
•
Medications (ketoconasole,
dilantin,phenobarbital,rifampin,etomidate,
metyrapone)
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Malignancy (Primary,metastatic)
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Adrenal hemorrhage (spontaneous,
traumatic,coagulopathy/heparin/coumadin)
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Familial
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Infiltrative diseases (amyloidosis,
sarcoidosis,hemochromatosis)
(Tumor,sarcoidosis,hemorrhage,
autoimmune,postoperative)
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Isolated adrenocorticotropic hormone
deficiency
Adrenal Insufficiency After Long-term
Corticosteroid Therapy
HPA axis suppresssion
• More than 20mg of prednisolone daily for more than 3
weeks, within the previous year
• Any patient who has clinical Cushing’s syndrome (from
any steroid dose)
Adrenal Insufficiency After Long-term
Corticosteroid Therapy
Safe withdraw dose and duration
• Dose equivalent to 5 mg/d or less of prednisolone
given for any length of time once daily in the
morning
• Any dose of glucocorticoid given for less than 3
weeks
Primary Adrenal Insufficiency
(Addison’s disease)
- Involve > 90% of the glands
Pathophysiology
• Gradual adrenocortical destruction
- Initial phase: Decreased adrenal reserve
Basal steroid secretion- Normal
Not increase in stress response
- Further loss of cortical tissue
Impair basal secretion of glucocorticoid and
mineralocorticoid
• Plasma ACTH elevation- Earliest and most sensitive indication
Anatomic Destruction of Gland
• Idiopathic atrophy: Autoimmune, leukodystrophy
• Surgical removal
• Infection: TB, Fungus, Virus esp. in AIDS
• Hemorrhage
• Invasion: Metastasis eg. CA thyroid, breast, kidney, lymphoma
Idiopathic Atrophy
• Most common cause 70-80%
• Autoantibody: adrenal cortex Ab, 21-hydroxylase Ab
• Isolated or associated with polyglandular autoimmune
syndrome
• PGA syndrome 2 types
• PGA type1- more common
• PGA type2
PGA Syndrome
• PGA type1 (Autoimmune Polyendocrinopathy- CandidiasisEctodermal Dysplasia)
- Autosomal recessive (no HLA association)
- Childhood onset
- 2/3 of these clinicals
:Chronic mucocutaneous candidiasis
:Chronic hypoparathyroidism
:Autoimmune adrenal insufficiency
- Other: Hypogonadotropic hypogonadism, DM type1,
Autoimmune thyroid disease, Lymphocytic hypophysitis,
Pernicious anemia, Chronic active hepatitis, Vitiligo, Alopecia
PGA Syndrome
• PGA type2
- Polygenic, asso. with HLA DR3,DR4
- Adult onset
- Primary adrenal insufficiency, Grave’s disease,
Autoimmune thyroiditis, DM type1, Primary
hypogonadism, celiac disease
Metabolic Failure in Hormone Production
• Congenital adrenal hyperplasia
. Inborn error of cortisol synthesis
. 5 types ( classified by type of enz. deficiency)
- Most common: 21-hydroxylase deficiency
- 2nd most common: 11-hydroxylase deficiency
• Drugs
- Enzyme inhibitors: Metyrapone, phenytoin,
barbiturate, ketoconazole, aminoglutethimide
- Cytotoxic agent: Mitotane
Slow Onset
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Auto-immune atrophy (cmst)
TBC
Metastatic CA (lung, breast, kidney) or lymphoma)
Systemic fungal infections (histoplasmosis, cryptococcosis,
blastomycosis)
Amyloid
Granulomatous disease
Late stage of AIDS (CMV, bacterial or protozoal infection or Kaposi’s)
Schilder's disease (hereditary leucodystrophy and adrenocortical
atrophy)
Wolman's disease (adrenal insufficiency, HSM,steatorrhoea with lipidfilled lysosymes)
Abrupt Onset
• Adrenal haemorrhage, necrosis or thrombosis in:
• meningococcal or other sepsis
• coagulation disorders
• as a result of warfarin therapy
• anti-phospholipid syndrome
Presentation
Highly variable
• Duration of disease
• Whether deficiency is primary or secondary
Potential Clinical Manifestations
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Glucocorticoid deficiency
Cardiovascular
hypotension ,impaired response to
catecholamines
Gastrointestinal
anorexia, nausea, weight loss,
abdominal pain, diarrhea
Cutaneous
hyperpigmentation (secondary to
ACTH precursors)
vitiligo (secondary to autoimmune
disease)
Muscular
fatigue,weakness,malasie
Neurologic confusion, apathy,
lethargy, psycosis
Mineralocorticoid Deficiency
• Cardiovascular
hypovolemia, decreased cardiac
output, impaired response to
catecholamines
Clinical Features of Primary
Adrenocortical Insufficiency
Weakness, fatigue, anorexia, weight loss
Hyperpigmentation
Hypotension
Gastrointestinal disturbances
Salt craving
Postural symptoms
Percent
100
92
88
56
19
12
Other Autoimmune Endocrinopathies
• Hypo and hyperthyroidism
• Type 1 DM
• Premature ovarian failure with ovarian auto-antibodies
• Primary hypoparathyroidism
• Pernicious anaemia
• Alopecia
• Mucocutaneous candidiasis
Acute Adrenal Crisis
Acute adrenal insufficiency
occurs in patients with Addison’s disease
who are exposed to the stress of infection,
trauma, surgery or dehydration
Clinical Features of Acute Adrenal Crisis
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Hypotension and shock
Fever
Dehydration, volume depletion
Nausea, vomiting, anorexia
Weakness, apathy, depressed mentation
Hypoglycemia
Laboratory Findings of Adrenal Insufficiency
Glucocorticoid
deficiency
Minerolocorticoid
deficiency
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Lymphopenia
Eosinophilia
Hypogycemia
Anemia
Hyponatremia
Hyperkalamia
Acidosis
Azotemia
Hypercalcemia
ECG: features are low voltage,vertical QRS axis, nonspesific ST-T
wave abnormalities
Diagnosis
Diagnosis of Adrenocortical Insufficiency
Since basal levels of adrenocortical steroids in either urine or
plasma may be normal in partial adrenal insufficiency, tests of
adrenal cortical reserve are necesseary to establish the diagnosis
Cortisol > 20 mg/day at any time of day -diagnosis very unlikely
Hemodynamic instability - cortisol < 20 mg/day - suspicious
ACTH Stimulation Test
• Performed at any time of day
• A baseline cortisol sample is obtained
• 250 mg/day synthetic ACTH (cosyntropin) is then administered
intravenously.
• Cortisol samples are drawn 30 and 60 min later.
• Plasma cortisol >18 mcg/dl excludes the diagnosis
Other Tests
• Insulin stress test,
• Corticotrophin releasing hormone test
• Metyrapone test
can be used to diagnose secondary adrenal
insufficiency
Tests to confirm 2ry adrenal insufficiency
• Prolong ACTH stimulation
- Baseline plasma cortisol
- Cosyntropin 250 ug iv q 8 hr for 48 hr.
: Primary adrenal insufficiency- plasma cortisol no change
: Secondary adrenal insufficiency- progressive increase in
plasma cortisol, and level >18 ug/dL
Tests to Confirm 2ry Adrenal Insufficiency
• Insulin induced hypoglycemia
- Suspected hypothalamic or pituitary disease
- Short acting insulin 0.05-0.1 u/kg at morning
- Blood for plasma glucose and cortisol at 30, 60, 90,
and 120 min
Normal response- if BG <40 mg/dl---cortisol> 18 ug/dl
( Avoid when hypoglycemia is contraindicated, 1ry
adrenal insufficiency, stroke, epilepsy)
Tests to Confirm 2ry Adrenal Insufficiency
• Short metyrapone test
- Metyrapone 30 mg/kg orally at 24.00 PM
- Blood for cortisol and 11-deoxycortisol at 8.00 AM
Normal- cortisol < 8 ug/dl
deoxycortisol > 7ug/dl
(Metyrapone not available in Turkey)
Plasma ACTH Level
Used to differentiate primary and secondary forms
Secondary adrenal insufficiency
plasma ACTH <30 pg/mL ( 7pmol/L)
Primary adrenal insufficiency
plasma ACTH >52 pg/mL
Suspected Adrenal Insufficiency
Rapid ACTH stimulation test
Abnormal
Normal
Adrenocortical
insufficiency
Exclude 1ry Adrenal
insufficiency
Plasma ACTH
Elevated
1ry Adrenal
insufficiency
Normal or low
2ry Adrenal
insufficiency
Abnormal
Decreased ACTH
reserve not excluded
Metyrapone or insulin
hypoglycemia testing
Normal
Exclude 2ry Adrenal
insufficiency
Differential Diagnosis
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CA
TB
Salt-losing nephropathy
Anorexia
Malnutrition
Severe GI disease
Malabsorption
Congenital adrenal hyperplasia
Treatment
Treatment of Acute Adrenal Crisis
• Glucocorticoid replacement
• Administer hydrocortisone sodium phosphate or sodium
succinate, 100 mg IV every 6 hour for 24 hours.
• When the patient is stable, reduce the dosage to 50 mg every
6 hours.
• Taper to maintenance therapy by day 4 or 5 and add
mineralocorticoid therapy as required.
• Maintain or increase the dose to 200-400 mg/d if complications
persist or occur.
• General and supportive measures
• Correct volume depletion, dehydration, and hypoglycemia with
intravenous saline and glucose.
• Evaluate and correct infection and other precipitating factors.
Regimen for Maintenance Therapy
• Hydrocortisone, 15-20 mg in AM and 10 mg orally at 4-5
pm
• Fludrocortisone, 0.05-0.1 mg orally in AM.
• Clinical follow-up:
• Maintenance of normal weight, blood pressure, and
electrolytes with regression of clinical features.
• Patient education plus identification card or bracelet.
• Increased hydrocortisone dosage during "stress.''
If Adrenal Crisis Suspected
• Blood drawn for cortisol and start
hydrocortisone immediately without waiting the
result
Or
• Intravenous ACTH stimulation test done and
start hydrocortisone immediately without
waiting the result
In Acute Adrenal Failure
• 100 mg hydrocortisone iv
• 100 mg iv every 6-8 hours
• Equivalent dose other corticosteroids
After 24 hours
• 25 mg hydrocortisone im every 8 hours
• Day 3 25 mg hydrocortisone im every 12 hours
• Day 4 oral replacement doses
Steroid
Glucocorticoid
Mineralocorticoid
Equivalent dose
0.8
25
0.8
Hydrocortisone
1
20
1
Prednisone
4
5
0.8
Prednisolone
4
5
0.8
Methypprednisolone
5
4
0.5
Triamcinolone
5
4
0
Paramethasone
15
2
0
Dexamethasone
30
0.75
0
Bethametasone
30
0.75
0
Aldosterone
0
400
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Cortisone
Fludrocortisone doses should be enough to abolish
• postural hypotension
• return Na and K to normal
• maintain plasma renin in upper normal range
• sustain well being
Fludrocortisone Doses
• Usually 50 - 200 mcg daily
• Excessive doses of fludrocortisone or hydrocortisone
may result in:
• unacceptable weight gain
• edema
• hypertension
Steroid and the surgical patient
Effect of Surgery
• Stress activates the HPA axis, increased
plasma ACTH and cortisol concentration.
• The degree of activation depend on the type of
surgery and anesthesia
• Cortisol increase to 75-150 mg/d,
normal: 15-20mg/d
Effect of Surgery
• The increase in cortisol: cariac output,
sensitivity to catecholamine, work capacity of
skeletal muscle, ability to mobilize energy
source.
• Greatest ACTH secretion: reversal of
anesthesia, during extubation, during the
immediated postoperative recovery period.
Steroid Coverage for Major Surgery
• Correct electrolytes, blood pressure, and hydration if necessary.
• Give hydrocortisone sodium phosphate or sodium succinate, 100
mg intramuscularly, on call to operating room.
• Give 50 mg intramuscularly or intravenously in the recovery room
and then every 6 hours for the first 24 hours.
• If progress is satisfactory, reduce dosage to 25 mg every 6 hours
for 24 hours and then taper to maintenance dosage over 3-5
days. Resume previous fludrocortison dose when the patient is
taking oral medications.
• Maintain or increase hydrocortisone dosage to 200-400 mg/d if
fever, hypotension, or other complications occur
Steroid Therapy Schedule For a Patient with Adrenal
Insufficiency Undergoing Surgery---minor surgery
• 100 mg of hydrocortisone is given intravenously with
the induction of anesthesia.
•
followed by usual maintenance dose (approximately
20 mg/d of hydrocortisone)
Corticosteroid Insufficiency in
Acutely Ill Patients
The Hypothalamic–Pituitary–Adrenal
Axis in Acute illness
• During severe illness, many factors can
impair the normal corticosteroid response.
Head injury;
CNS depressants
Pituitary infarction
Ketoconazole
Adrenal hemorrhage in
septicemia or coagulopathy
Extensive
destruction
by tumor or
infection
High level of inflammatory
cytokines in sepsis p’t
directly inhibit adrenal
cortisol synthesis
The Hypothalamic–Pituitary–Adrenal
Axis in Acute illness
• Develop during an illness
• Transient
• “Functional adrenal insufficiency”
-- no obvious structral defects in HPA axis
• “Relative adrenal insufficiency”
-- insufficient to control the inflammatory
response
Diagnosis of Corticosteroid
Insufficiency during Acute illness
• Corticosteroid insufficiency associated with
acute illness
-- difficult to discern clinically, but there are
some features that suggest the diagnosis.
Features suggesting
corticosteroid
insufficiency
common in patients with acute
severe illness.
Easy been masked by fluid
replacement, especially in ICU
Relatively uncommon
Laboratory Investigations
Randomly measured cortisol levels
• More useful would be the identification of a
minimal threshold level and a maximal
threshold level.
• 15 µg/dl (10 µg/dl to 34 µg/dl) best identifies
persons with clinical features of corticosteroid
insufficiency or who would benefit from
corticosteroid replacement
Laboratory Investigations
Corticotropin stimulation test
IV or IM 250 µg of Cosyntropin
Check plasma cortisol levels
0, 30, ( 60 ) mins after administration
Laboratory Investigations
Corticotropin stimulation test
• Prognostic implications
-- < 9 µg /dl  increased risk of death.
• > 34 µg /dl: unlike.
• <15 µg /dl: likely.
In Summary
• Adrenal failure can be primary or
secondary
• Clinical features can be variable
• Diagnosed by basal cortisol and ACTH
stimulation test
• Treated with glucocorticoids +
mineralocorticoids